Syntheses, crystal structures and Hirshfeld surface analyses of four molecular salts of amitriptynol

The syntheses and low-temperature crystal structures of four organic salts of amitriptynol, a common impurity in the anti-depressant drug amitriptyline, are described.

The syntheses and crystal structures of four salts of amitriptynol (C 20 H 25 NO) with different carboxylic acids are described. The salts formed directly from solutions of amitriptyline (which first hydrolysed to amitriptynol) and the corresponding acid in acetonitrile to form amitriptynolium [systematic name: (3-{2hydroxytricyclo[9.4.0.0 3,8 ]pentadeca-1(11), 3,5,7,12,14-hexaen-2-yl}propyl) (IV). Compound (III) crystallizes with two cations, two anions and six water molecules in the asymmetric unit. The different conformations of the amitriptynolium cations are determined by the torsion angles in the dimethylamino-propyl chains and the -CH 2 -CH 2 -bridge between the benzene rings in the tricyclic ring system, and are complicated by disorder of the bridging unit in II and III. The packing in all four salts is dominated by N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds. Hirshfeld surface analyses show that the amitriptynolium cations make similar inter-species contacts, despite the distinctly different packing in each salt. Amitriptynol,C 20 H 25 NO,propyl]-10,11-dihydro-5H-dibenzo [a,d][7]annulen-5ol, is a derivative and common impurity (designated 'amitriptyline impurity B 0 ) of amitriptyline, C 20 H 23 N. Amitriptyline is a tricyclic antidepressant agent, which also has analgesic properties with sedative effects. Amitriptyline affects certain chemical messengers (neurotransmitters) that communicate between brain cells and help regulate mood. It is used in the treatment of depression, neuropathic pain, and migraine.

Chemical context
A review of the pharmacological properties and therapeutic use for chronic pain of amitriptyline was published by Bryson & Wilde (1996). A comprehensive review of amitriptyline for the treatment of fibromyalgia was given by Rico-Villademoros et al. (2015). In a systematic review, Thompson & Brooks (2015) discussed the use of topical amitriptyline for the treatment of neuropathic pain. A brief review of the pharmacology of amitriptyline and clinical outcomes in treating fibromyalgia was given by Lawson (2017). Analytical methods for the determination of amitriptyline and its metabolite nortriptyline were reviewed by Khatoon et al. (2013). Mol-ecular insights from single-crystal X-ray diffraction and DFT calculations of -cyclodextrin encapsulation of nortriptyline HCl and amitriptyline HCl were published by Aree (2020a).
Our goal was to prepare molecular salts of amitriptyline, but the amitriptyline free base is susceptible to hydrolysis, owing to its aliphatic double bond attached to the central sevenmembered ring (Henwood, 1967). Consequently, the amitriptyline hydrolysed to amitriptynol, which then formed salts with the organic acids. Perhaps surprisingly, any such salts have thus far been absent from the crystallographic literature. This paper reports the crystal structures of four amitriptynolium (C 20 H 26 NO + ) salts: 4-methoxybenzoate monohydrate (I), 3,4-dimethoxybenzoate trihydrate, (II), 2-chlorobenzoate (III) and thiophene-2-carboxylate monohydrate (IV).

Structural commentary
Salts I and IV crystallized as monohydrates, and II as a trihydrate; only salt III is anhydrous (see Figs The molecular structure of II showing 50% displacement ellipsoids. Hydrogen bonds are drawn as dashed lines. Only the major disorder component is shown.

Figure 3
The molecular structure of III showing 50% displacement ellipsoids. Hydrogen bonds are drawn as dashed lines. Only the major disorder component is shown.

Figure 4
The molecular structure of IV showing 50% displacement ellipsoids. Hydrogen bonds are drawn as dashed lines. Only the major disorder component is shown.

Figure 1
The molecular structure of I showing 50% displacement ellipsoids. Hydrogen bonds are drawn as dashed lines. their chemical similarity (i.e., the same cation and similar sized aromatic carboxylate anions), the crystal structures of I-IV are notably distinct, each having different space-group symmetries (Pn for I, Cc for II, P2 1 /n for III, and P2 1 2 1 2 1 for IV).
Although only IV has a Sohncke space group, its structure was twinned by inversion, with major:minor twin fractions of 0.70 (7):0.30 (7), so any discussion of absolute configuration is moot.
The conformations of the amitriptynolium cations are determined by the torsion angles in the dimethylamino-propyl chains and by the C6-C7-C8-C9 torsion angles in the long bridge between the benzene rings of the tricyclic ring system, and are complicated by cation disorder in II and III. All conformation-defining torsion angles are given in Table 1, but further description is limited to the major disorder components. From Table 1 and Figs. 1-4, it is evident that the cation geometries in I, III, and IV are broadly similar. The two independent cations in II, however, are self-similar, but different from I, III, and IV, primarily evidenced by the C16-C17-C18-N1 torsion angle, which is anti in both cations of II, but gauche in I, III, and IV. In each case, the tricyclic unit of the cation adopts a 'butterfly' conformation with dihedral angles between the pendant benzene rings of 62.01 (9) (I), 69.30 (16) and 71.06 (13) (II), 57.21 (10) (III) and 50.51 (8) (IV). In every case, the -OH group attached to C15 is in an equatorial orientation and the pendant alkyl chain is axial.
The 4-methoxybenzoate anion in I is largely planar, with maximum deviation from planarity of 0.1216 (15) Å , caused by a C24-C25-O4-C28 torsion angle of À7.5 (2) for the methoxy group. In II, the 3,4-dimethoxybenzoate anions are also close to planar. In the 'A' anion, C29A is offset by 0.229 (2) Å from the mean plane, for a C26A-C25A-O5A-C29A methoxy torsion of 13.6 (3) , while for the 'B' anion, the largest deviation is 0.2264 (16) Å for O2B, due to the dihedral angle between the benzene ring and the carboxylate group of 10.43 (15) . The 2-chlorobenzoate anion in III is disordered by a $180 flip, giving major:minor component occupancies of 0.9600 (15):0.0400 (15). The two components are, however, far from planar as a result of steric hindrance by the chlorine substituent; the dihedral angles between the chlorobenzene and carboxylate groups being 57.82 (11) and 56.4 (5) for the major and minor parts, respectively. In IV, the thiophene-2carboxylate anion is also disordered, with major:minor occupancies of 0.899 (3):0.101 (3), but the components are again largely planar; the maximum deviations being for O3 in each, at 0.167 (3) Å (major) and 0.14 (2) Å (minor), resulting from dihedral angles between the thiophene rings and carboxylate groups of 12.3 (6) (major) and 11 (5) (minor).

Supramolecular features
The dominant supramolecular features in all four salts are N-HÁ Á ÁO hydrogen bonds between the cationic [R 3 N-H] + moiety and the anion carboxylate groups, plus O-HÁ Á ÁO hydrogen bonds involving the amitriptynolium cation O-H group as donor to a carboxylate acceptor in III and to water molecules in I, II, and IV. These hydroxyl groups are effectively shielded from accepting strong hydrogen bonds by the adjacent benzene rings of the amitriptynolium fused ring systems in each case. The strong hydrogen bonds are augmented in all four structures by a few weaker C-HÁ Á ÁO contacts. Table 1 Conformation-defining torsion angles ( ) in I-IV. atoms torsion angle geometry 68.6 (2) gauche In I, the main packing motifs are infinite chains of N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen-bonded cations, anions, and water molecules that extend parallel to the a-axis direction. These are shown in Fig. 5 and quantified in Table 2, along with their attendant symmetry operations.
Owing to the presence of two copies each of cation and anion, plus six water molecules in the asymmetric unit (Z 0 = 2), the packing in II is the most complex of the four salts. However, the most obvious supramolecular feature, an R 4 4 (8) ring of water molecules, is evident in the ellipsoid plot of its asymmetric unit (Fig. 2). These rings of four water molecules are hydrogen bonded to the anion carboxylate groups (via O1W and O4W to O3A and O2B, respectively), and via O2W and O3W to (À1 + x, y, z) and (1 + x, y, z) translation-related anion carboxylate groups (Table 3). The anions in turn act as hydrogen-bond acceptors to the cations (via O2A to N1A and O2B to N1B). The remaining water molecules accept hydrogen bonds from the cation hydroxyl groups (O1A to O5W and O1B to O6W), also shown in Fig. 2. In addition to the hydrogen-bonded motifs shown in Fig. 2, water molecule O5W takes part in bifurcated O-HÁ Á Á(O,O) hydrogen bonding to both methoxy groups of a translation-related (x, y, À1 + z) anion, and similar bifurcated hydrogen bonding occurs between water molecule O6W and a translation-related (À1 + x, y, 1 + z) anion. The net result gives layers of cations and layers of anions parallel to the ac plane interspersed with and separated by the water molecules (Fig. 6). These layers stack along the b-axis direction to build an intricate threedimensional framework. Given its complexity and the size of the unit cell [the b-axis is 55.2061 (19) Table 2 Hydrogen-bond geometry (Å , ) for I. Symmetry codes: (i) x À 1; y; z; (ii) x þ 1; y; z; (iii) x À 1 2 ; Ày þ 1; z þ 1 2 .

Figure 6
A packing plot of II viewed down the a-axis direction showing alternating layers of amitriptynolium cations (green) and 3,4-dimethoxybenzoate anions (blue), interspersed with water molecules (red). Hydrogen bonds are drawn as dotted lines. Table 3 Hydrogen-bond geometry (Å , ) for II.  (3) 169 (3) Symmetry codes: (i) x þ 1; y; z; (ii) x À 1; y; z; (iii) x; y; z À 1; (iv) x À 1; y; z þ 1. Table 4 Hydrogen-bond geometry (Å , ) for III. Symmetry codes: (i) x þ 1; y; z; (ii) Àx þ 1; Ày þ 1; Àz þ 1. molecular graphics program such as Mercury (Macrae et al., 2020). The hydrogen bonding in III is the simplest of the four salts because there are no water molecules involved. N-HÁ Á ÁO hydrogen bonds connect cation to anion within the (chosen) asymmetric unit and O-HÁ Á ÁO hydrogen bonds connect cations to anions in adjacent unit cells, to form chains that extend parallel to the a-axis, as shown in Fig. 7 and Table 4. The main supramolecular constructs in IV are hydrogenbonded chains that propagate parallel to its a-axis, broadly similar to those in I (Fig. 8, Table 5).

Figure 7
A partial packing plot of III viewed down the b-axis direction. The N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds are drawn as solid dashed lines. Minor disorder and hydrogen atoms not involved in strong hydrogen bonds are not shown. between 22.8% coverage in I to 27.2% in II. The only other double-digit percentage coverages are for HÁ Á ÁO/OÁ Á ÁH contacts, which range from 11.2% in IV to 12.9% in III. All other types of contact involving the cations are negligible.

Synthesis and crystallization
Solutions of commercially available (RL Fine Chem, Bengaluru, India) amitriptyline (100 mg, 0.360 mol) in methanol (10 ml) were mixed with equimolar solutions of the appropriate acid in acetonitrile (10 ml   Absolute structure parameter 0.08 (7) 0.00 (7) -0.30 (7) The resulting solutions were stirred for 30 minutes at 333 K and allowed to stand at room temperature. X-ray quality crystals formed on slow evaporation of solutions in ethanol:acetonitrile (1:1) after a week for all four compounds. The melting points are 367-369 K (I), 359-361 K (II), 410-412 K (III) and 373-376 K (IV).